Nitrobenzisoxazoles



Patented Jan. 20, 1953 NITROBENZIS OXAZOLES Raymond 0. Clinton, North Greenbush, and Stanley C. Laskowski, Menands, N. Y., assignors to Sterling Drug Inc., New York, N. Y., a corporation of Delaware No Drawing. Application September 5, 1951, Serial No. 245,245

22 Claims. 1

This invention relates to tertiary-aminoalkyl esters and amides of 6-nitrobenzisoxazole-3-carzN O/N where Y is O or NH, X is a lower alkylene radical and NRR1 is a tertiary-amino radical. These compounds are useful as intermediates in the preparation of other organic compounds. The esters (where Y is for example, undergo a novel rearrangement reaction to form 4-nitro-2- (tertiary-aminoalkoxy)benzonitriles. This rearrangement process is disclosed and claimed in our copending application Serial No. 245,250, filed September 5, 1951. The 4-nitro-2(tertiaryaminoalkoxy benzonitriles are disclosed and claimed in our copending application Serial No. 245,243, filed September 5, 1951.

In the above general formula, the lower alkylene radical designated as X has preferably two to four carbon atoms and has its two free valence bonds on different carbon atoms. Thus, X includes such examples as and thelike. The tertiary-amino radical shown above as NRR1 comprehends dialkylamino radicals where R and R1 are lower alkyl groups, alike or difierent, and each alkyl group'having one to six carbon atoms, such dialkylamino radicals including dimethylamino, diethylamino, ethylmethylamino, diisopropylamino, ethyl-n-propylamino, di-n-butylamino, di-n-hexylamino, and the like. Further, the tertiary-amino radical designated as NRR1 encompasses saturated N- heteromono-cycllc radicals having five to six ring atoms, illustrated by examples such as l-piperidyl; (lower alkylated) -l-piperidyl such ,as 2- methyl-l-piperidyl, 3-ethyl-l-piperidyl, 4-methyl-l-piperidyl, 2,6-dimethyl-1-piperidyl; l-pyrrolidyl; (lower alkylated) -1-pyrro1idyl such as 2- methyl-l-pyrrolidyl, 2,5-dimethyll-pyrrolidyl; 4-morpholinyl; and the like.

The compounds of our invention are prepared by reacting a lower alkyl fi-nitrobenzisoxazole-B- carboxylate with a compound having the formula H-Y-X-NRRi, where Y, X and NRRi' have the meanings given hereinabove. The reaction is carried out preferably using methyl fi-nitrobenzisoxazole-3-carboxylate because of its ease of preparation. Where Y is O. that is, where H-Y-X-NRR1 is a tertiary-aminoalkanol, the re sulting product is a tertiary-aminoalkyl 6-nitrobenzisoxazole-3-carboxylate; Where Y is NH, that is, where H-Y-X-NRRi is a tertiary-aminoalkylamine, the resulting product is an N-(tertiaryaminoalkyl) -6-nitrobenzisoxazole -3- carboxam ide. The reaction is carried out preferably by heating a mixture of methyl G-nitrobenzisoxazole-3-carboxylate and a tertiary-aminoalkanol or a tertiary-aminoalkylamine. Illustrative of the reaction is the formation of 2-diethy1aminoethyl 6-nitrobenzisoxazole-3-carboxy1ate and N- (2-diethylaminoethyl) 6 nitrobenzisoxazole-3- carboxamide by heating methyl 6-nitrobenzisoxazole-3-carboxylate with Z-diethylaminoethanol and 2-diethylaminoethylamine, respectively The reaction is carried out preferably using a nonpolar inertsolvent, such as benzene, toluene, xylene, a petroleum ether fraction, etc. Best yields of the tertiary-aminoalkyl 6-nitrobenzisoxazo1e-3-carboxylates were obtained when a heating period of about thirty minutes was used and when the methanol formed by the reaction was removed from the reaction mixture by distillation. While these conditions are desirable for obtaining best yields of said esters, the. reaction can be carried out without using them, but with a sacrifice in yield of the esters. A prolonged heating period is undesirable since this would result in rearrangement of the tertiary-amino 6- ni-trobenzisoxazole-3-carboxylates to produce the related 4-nitro 2 (tertiary aminoa1koxy)ben zonitriles, this rearrangement process having been referred to hereinabove.

The tertiary-aminoalkyl 6-nitrobenzisoxazole- 3-carboxylates are relatively unstable in their free base form even when simply exposed to air at room temperature; even under these mild conditions they tend to slowly undergo said rear-- rangement reaction to give small quantities of the resulting 4-nitro-2-(tertiary-aminoalkoxy) benzonitriles. However, these esters, in the form of their acid addition salts, are quite stable. Therefore, in practicing our invention, we prefer to isolate the tertiary-aminoalkyl 6-nitrobenzisoxazole 3-carboxylates in the form of their hydrochloride addition salts.

The N (tertiary-aminoalkyl) -6 -nitrobenzisoxazole-3-carboxamides of our invention are very stable whetherin the form of their free bases or as their acid addition salts.

Our invention comprehends the tertiary-aminoalkyl esters and'amides of 6-nitrobenzisoxazole- 3-carboxylic acid whether in the form of their free bases or in the form of their salts with rela tively non-toxic organic or inorganic acids. In practicing our invention, we found it convenlent to isolate. our compounds in the form of their 4 lower alkyl 6nitrobenzisoxazole-3-carboxylates are formed. Thus, using n-propanol, n-butanol or isobutanol there is obtained; respectively, n-

hydrochlorides- However, other? a d addition propyl G-nitrobenzisoxazole-d-caliboxylate, nsalts are within the scope of our invention. Such 5 butyl 6-nitrobenzisoxazole-3-carboxylate or 1 additional salts including the hydrobromides, sulbutyl 6-nitrobenzisoxazole-3carboxy1ate. fates, hosphates, citrates, sulfamates, tartrates. I succin tes, acetates, benzoates, oleates; and the rertzary'ammoalkyl 6"mtmbenzzsomzole's' like. carbowylates specific embodiments of ourimlentmn' streams" Preparation of these esters, in the form of their t ted by the following exampleu hydrochlorides; is'illustrated by the following gen- I, Lower alkyl fi-nitrobenzisorazole-3-carborylate eral procedure. A mixture of 44.4 g. (0.2 mole) of. methyl 6.-nitrobenzisoxazole-3-carboxylate. Methyl 6-nitrobenzisoxazole-3-carlooxylate was 0227111018 of the appropriate tert1ary amin0a1ka p a from methyl ledinitrophenylacetete 15 noland, 350ml. of dry toluene was distilled slowly according to the method. of Borsche [Ann. 390; 1 through a Vacuum jacketed vigreux commn (1912)]. In order to achieve consistently the surmounted by a totalerefiux variable take ofl yield" 85% reportedr by Borschei it was found distillation head. During one-half hour twelve necessary: to use freshly prepared butyl nitrite and to sixteen m1. of distillate were collected, the final an ini'fiiel mixingtemperature of the distillate temperature being 105 c; The pale components- This' closure procedure was yellow-brown still residue was decolorized using also tried usingother lower alkyl esters of 2,4- decolorizing charcoal and the toluene. was dimtrophenylacetic acid, however with poor moved in vacuo. The residue was dissolved in sultse Using H-PYOPY'L isopropyl n-butyl ethyl acetate and the solution. was treated with ters 234-dinitropheny1acetic acid" in their an excess of 20% ethereal hydrogen chloride. The spective'alkanolsassolvents, only tarry pro precipitated white solid was, recrystallized from were: obtained? Using ethyl zil'dimtrophenyl' ethanol or isopropanol. The yields of the purified acetatem ethanol yield of about 20% of ethyl tertiary-aminoalkyl 6-nitrobenzisoxazole-3 cars'mtrobenzisoxazole'3'carboxylate was obtained boxylates in the form o-f their hydrochlorides were This esterrecrystallized as yellow needles from 5 -75 ethanol Thesame productsresult when the above proe AnaL Cake for} cedure is followed but using other alkyl esters CitHaNeOs C; -0 z, 5.91; ND. .9} such as ethyl or n-butyl' 6 -nitrobenzisoxazole-3- 5 i 604; 35 carboxylate in place of methyl o' nitrobenziso-xa- NOR: s l nitro i d i r l%ti i chgfigig me gelggifiea'cgict acgd a 1 21 1 522253? procedure was: followed using No stands for total nitrogen as determined by the 2 diethy1aminoethan01 as t t t i mms'methqd" alkanol, the resulting product was 2-diethy1- 'b methodv p p g the lower alkyl 40 aminoethyl 6-nitrobenzisoxazole-3-carboxyla;teas G-nitrobenzisoxazole-B carboxylates other than the hydrochloride Useof other tertiaryammoe methyl ester is a -by the ester exchange alkanols yield the corresponding tertiary-aminoreaction of methyl 6-HitIObBIIZiSOXaZOIE-3C91- alkyl esters in the form of their hydrochlorides boxylate and the appropriate lower alkanolg. as as iven in: Table Abelow illu ra d in h foll w ng pr p ra ion of hy The free base form of a given ester was con- 6-nitrobenzisoxazole-3-carboxylateusing ethanol. veniently prepared by dissolvin a portign 9f t A m x of 0'g.,of.mlethyl firnitrobenzisoxazolerhydrochlOride salt in ice; water and treating the '0 y at 300' m1. of anhydrous ethanol and solution with an excess of cooled, saturated so- 21ml: of triethylamine wasboil'edgently. for twenty dium bicarbonate solution. The precipitated oily minutes; Th clear, solution was diluted while or crystalline base was taken up in cold ethyl hotwithen qualvolume ofwat ecooled, filtered acetate, the extractwasdried and the tertiaryandi'the. product was. washed with Water., The aminoalkyl fienitrobenzisoxazole-3-carboxy1ate resultingmateriall after drying, wasagain treated was obtained by removing. the. ethyl. acetatein with anhydrous ethanol and triethylamine as vacuo. before. There was thus obtained anearly quan- TABLE-A. titativeyield of ethyl 6-nitrobenzisoxazole-3i-care- A t boxylate, M. P. 99.0100.0 c. WOOQWEWRRPHCI Following this; procedure but using otherlower alkanols in place. of ethanol, the corresponding 0 Analyses a NRR; Formula; 01 N Calcd Found Calcd. Found 2; mom 112. 0-173. 0 Cl2H'1a '3O5- C] 11.2% 11.22 2. N(CzH5 )z l51.8l53.0 C14Hl1NaO5 -HCI 10.31 10.32 4.07 4.04 a N(C.2Hs)z 151. 5-151.s OisHisNaQs.HCl- 9.91 9,97 3.92 3.9.9, 2 051110 160. l-l6l.0 C15H N 0 .H(3l 9.97 10.02 3.94 3:84 2 Notifie "151.0-15L5 C1BH1BN305.HCI 9.59 9.69 3.79. 3.74- 3. NCsHw 189. 9-190. 3 C16H19N305.HC1 9. 59 9. 44 3. 79 3. s CtHrz 157. 8-l58.7 C11H2|N3O5.HC1 9.24 9. 20 3:65 3.63

Withdecomposition;

dyl. NCtHn=2-methyl-l -piperidyl;

1. Additional tertiary-aminoalkyl 6-nitrobenzlsoxazole-3-carboxylates, in the form of their hydrochloride addition salts, which can be prepared according to the foregoing procedure include the following: 3-(2,6-dimethyl-1-piperidyl)propyl 6-nitrobenzisoxazole-3-carboxylate; 3- (4-morpholinyl) propyl 6-nitrobenzisoxazole- 3-carboxylate 3-(1-pyrrolidyl) propyl 6-nitrobenzisoxazole 3-carboxylate; 2-(2,5-dimethyl- '1 pyrrolidyl) ethyl 6-nitrobenzisoxazole-3-carboxylate; 4-dimethylaminobutyl G-nitrobenzisoxazole-3-carboxylate; 3-dimethylamino-2-propyl 6 nitrobenzisoxazole B-carboxylate; 2-(di-nbutylamino) ethyl 6 nitrobenzisoxazole 3-carboxylate; 2-(3-ethyl-l-piperidyl)ethyl G-nitrobenzisoxazole 3 carboxylate; 3-(4-methyl-1- piperidyDpropyl 6 nitrobenzisoxazole 3-earboxylate 3- (Z-methyl-l-pyrrolidyl) propyl 6-nitrobenzisoxazole-3-carboxylate; and the like.

III. N (tertiary-aminoalkyl) -6-fiitrobenzisoa:a zoZe-3-carboazamides Preparation of these amides is illustrated by the following general preparation. A mixture of 44.4 g. (0.20 mole) of methyl G-nitrobenzisoxazole-3-carboxylate, 0.3 mole of a tertiary-aminoalkylamine and 300 ml. of toluene was refluxed for about five to nine hours. The toluene was removed in vacuo and the residual crystalline product was washed thoroughly with n-pentane. The insoluble residue was dissolved in ethyl acetate, the solution was decolorized using decolorizing charcoal, and there was added to the filtrate an excess of 20% ethereal hydrogen chloride. The resulting crystalline hydrochloride was recrystallized from ethanol. The yields of the purlfied hydrochlorides varied from 70-85%. The hydrochlorides were converted to the base using aqueous potassium carbonate solution, and the resulting N-(tertiary-aminoalkyl) -6-nitrobenzisoxazole 3-carboxamides were recrystallized from n-heptane.

The same products are obtained when the above procedure is followed but using other alkyl esters such as ethyl or n-butyl fi-nitrobenzisoxazole-B-carboxylate in place of methyl 6-nitrobenzisoxazole-3-carboxylate.

When the above procedure was followed using, as the tertiary-aminoalkylamine, Z-diethylaminoethylamine, 3-diethylaminopropylamine, 4-diethylaminobutylamine and 3-diethylamino-2- hydroxypropylamine, the resulting products were, respectively, N- (2 diethylaminoethyl) -6-nitrobenzisoxazole 3 carboxamide hydrochloride, M. P. 2210 228.? (3. (cor.) EAnal. Calcd. for C14H18N4O4.HC1Z NNO2, 4.09; CI, 10.34. Found: NNO2, 4.32; Cl, 10.44] N-(3-diethylaminopropyl) 6-nitrobenzisoxazole-B-carboxamide hydrochloride, M. P. 232.5--233.5 C. with decomposition.

benzisoxazole 3 carboxamide hydrochloride,

M. P. 209.0-209.7 C. (cor.) EAnal. Calcd. for Ci5H20N4O5l-IC1: NNO2, 3.76; Cl, 9.51. Found:

NNO2, 3.98; 01, 9.66].

Treatment of the foregoing N-(tertiary-amino alkyl) -6-nitrobenzisoxazole-3-carboxainide hydrochlorides with aqueous potassium carbonate solution, as described above, yielded the following respective N-(tertiary-aminoalkyl) -6-nitrobenzisoxazole-3-carboxamides in their free base form: N (Z-diethyl-aminoethyl)-6-nitrobenzisoxazole-3-carboxamide, M. P. 61.0-63.0 C. (cor.) [AnaL Calcd. for C14H1sN4O4: NBA, 4.57. Found: NBA, 4.58] N-(3-diethylaminopropyl) -6-nitrobenzisoxazole-3-carboxamide, M. P. 89.0-89.5 C. (cor.) [Anal Calcd. for C15H2UN4OA: NBA. 4.37; NN02, 4.37. Found: NBA, 4.36; Nno 4.14]; N-(4- diethylaminobutyl) 6-nitrobenZisoxazole-3ecar.. boxamide, M. P. 59.0-60.0 C. (cor.) [Anal. Calcd. for Ciel-122N404: C, 57.47; H, 6.63; NBA, 4.19. Found: C, 57.54; H, 6.58; NBA, 4.14]; and N-(3-diethylamino-Z-hydroxypropyl) -6-nitrobenzisoxazole-3-carboxamide, M. P. 119.8120.7 C. (cor.) [Anal Calcd. for C15H20N4051 NBA, 4.16. Found: NBA, 4.18].

NBA stands for basic amino nitrogen as determined by iiiggation with perchloric acid in glacial acetic acid solu Additional (tertiary aminoalkyl) 6 nitrobenzisoXaz0le-3-carboxamides which can be prepared according to the foregoing procedure using the appropriate tertiary-aminoalkylamine include the following: N-[3-(2-,6-dimethyl-lpiperidyhpropyll 6 nitrobenzisoxabole 3 carboxamide; N-[3-(4 morpholinyDpropyll- 6 nitrobenzisoxazole 3 carboxamide; N- [3 (1 pyrrolidyDpropyll 6 nitrobenzisoxazole S carboxamide; N-[2-(2,5 dimethyl l pyrrolidybethyll 6 nitrobenzisoxazole- 3 carboxamide; N (4 dimethylaminobutyl) 6 nitrobenzisoxazole 3 carboxamide; N-(3-- dimethylamino 2 propyl) 6 nitrobensisoxazole 3 carboxamide; N [2 (di -.n butylamino)ethyll 6 nitrobenzisoxazole 3 carboxamide; N [2 (3 ethyl 1 piperidyhethyl] 6 nitrobenzisoxazole 3 carboxamide; N [3 (4 methyl 1 piperidyDpropyl] 6 nitrobenzisoxazole 3 carboxamides; N [3 (2 methyl 1 pyrrolidyDpropyll 6 nitrobenzisoxazole 3 carboxarnide; and the like.

Our N-(tertiary-aminoalkyl) -6-nitrobenzisoxazole-3-carboxamides can be converted into their quaternary ammonium salts as illustrated by the following examples: A mixture of 5 g. of N (3 diethylaminopropyl) 6 nitrob'enzisoxazole-3-carboxamide, 20 ml. of methyl iodide, 50 ml. of ethyl acetate and 25 ml. of absolute ethanol was refluxed for one and three-quarter hours. 7 the precipitated product was collected and washed well with ethyl acetate. 3 Two recrystallizations of this precipitate from ethanol'yielded, as a whitecrystalline product, N-(3-diethylaminopropyl) 6- nitrobenzisoxazole 3 carboxamide methiodide, M. P. 2040-2060 C. (cor.) when dried over phosphorus pentoxide at C. and 0.01 mm. for four hours.

Anal. Calcd. for C15H20NA04'CH8I: NNOQ, 3.03; I, 27.46. Found: NNogy 3.21; I, 27.19.-

Following the foregoing procedure but using N (3 diethylamino 2 hydroxypropyl) 6 .nitrobenzisoxazole 3 carboxamide instead of M. P. 174.5 175.8 C. (cor.). .Anal. Calcd. for C1 H N O -CH I:

The reaction mixture was cooled and 7 We-claim? 1 A compound having the. formula where-Y is a member of the group consisting of Qand. NH, .X is a; lower alkylene. radical whose twofree; valence. bonds are on different carbon atoms and NRRi is atertiary-amino radical selected from the. group consisting of lower dialkylamino,.1J-piperidyl, (loweralkylated) -1-piperidy1, L-pyrrolidyl, (lower. alkyla-ted) l-pyrro.lidyland l-morpho-linyl.

2. An esterhaving the. formula.

where X is'a lower alkylene radical. whose two free valence bonds are ondifferent carbon atoms.

3; 'A-n ester having the formula.

where'X is a lower alkylene. radical whose two free-valence bonds are on different carbon atoms.

4. An ester having the formula.

where X is alower alkylene radical whose-two free valence bonds are on different carbon atoms and NRRI is a (lower alkylated)-1-piperidyl radical.v

5. An ester having the formula N 2 I where. X is a lower. alkylene. radical whose two free valence bonds are on different carbon atoms and NRR1 is a Z-methyl-l-piperidyl radical.

6. Anester having the. formula where, X is a lower alkyleneradical' whosgtwo free, valence bonds are on different carbon atoms and. NRR1 is a. l-piperidyl radical.

7. A process of preparing a compound having the formula where Yjis a member of the group consisting of O and NH, X is a lower alkylene radical Whose two free valence bonds are on different carbon atoms and NRR1 is a tertiary-amino radical selected'from the group consisting of lower dialkylamino, l-piperidyl, (lower alkylated) -l-piperidyl, l-pyrrolidyl, (lower alkylated).--1-pyrrolidyl. and i-morpholinyl, which comprises reactinga lower alkyli 6i-nitroberizisoxazole--.-3-carJo.oxylate:.withv a compound having: the. formula..H YX.iNRR1.

8. A process of' preparing an ester having. the formula where- X is a. lower alkyleneyraidical whose two free valence bondsareon different carbon atoms, which comprises reacting methyl 6-nitrobenzisox azole-3-carboxy1atewith a dialkylaminoalkanol havingthe formula HOX.N(lower alkyl) 2.

9 A process of preparing, an: ester: having the formula.

OzN

where X is a lower alkylene radical whose two free valence bonds are on different carbon atoms, whichcomprises reacting methyl 6-nitrobenzisoxazole-3-carboxylate with adiethylaminoalkanol having the formula HOXN(C2H5) 2;

10. A process of preparing an ester'having'the formula where X'is a lower alkylene'. radical whose two free valence bonds. are on different carbon atoms and NRRL is a, (lower'alkylatedi-l-piperidyl. radical, which comprises reactingmethyl 6-nitrobenzisoxazole-S-carboxylate with a tertiary-aminoalkanol having the formula HOX-NRR1.

1,1. A process of preparing an ester having the formula.

where X'is a lower alkylene. radical. whose. two free. valence bonds. are. on different carbon atoms vandNRRi is a Z-methyl-l-piperidyl radical, which comprises reactin methyl G-nitrobenzisoxazole- 3-carboxylate with a tertiary-aminoalkanoli'havihgthe formula HO-XNRR1.

12. A process of preparing a compound" havn the formula" 18. A process of preparing Z-diethylaminoethyl 6-nitrobenzisoxazo1e-3-carboxylate which comprises reacting methyl G-nitrobenzisoxazole- E-carboxylate with Z-diethylaminoethanol.

19. A process of preparing 3-diethy1aminopropyl 6-nitro1oenzisoxazo1e-3-carboxy1ate which comprises reacting methyl G-nitro'benzisoxazole- 3-carboxylate with 3-diethy1aminopropano1.

20. A process of preparing 2-(1-piperidyl) ethyl 6-nitrobenzisoxazole-3-carboxylate which comprises reacting methyl 6-nitrobenzisoxazo1e-3- carboxylate with 2-(1-piperidy1) ethanol.

21. A process of preparing 3-(1-piperidyD- propyl 6-nitrobenzisoxazole-3-carboxy1ate which comprises reacting methyl 6-nitrobenzisoxazo1e- 3-carboxy1ate with 3-(1-piperidy1) propanol.

22. A process of preparing 2-(2-methyl-1-piperidyD-ethyl 6-nitrobenzisoxazole-3-carboxy1ate which comprises reacting methyl G-nitrobenzisoxazole-B-carboxylate with 2-(2-methyl-1-piperidyl) ethanol.

RAYMOND O. CLINTON. STANLEY C. LASKOW SKI.

No references cited. 

1. A COMPOUND HAVING THE FORMULA 